tbuckley/cabot-search huggingface dataset:
Abstract 1860: NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to cause cell death in CDK4i-resistant breast cancer
Authors: Stacy Wister Blain, Arianna Chand, Lina Pedraza-Ortiz, Allison VanInwegen, Lingyu Yan, Yun Wu, Grace Chen, Irina Jilishitz
Journal: Cancer Research (2022)

Abstract Resistance to cyclin D-cdk4/6 inhibitors (CDK4/6i) is frequently caused by compensatory CDK2 activity. We have developed a novel strategy to kill CDK4i resistant tumor cells using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. IpY is specific for p27, and this reduces toxicity relative to that seen with the small molecule ATP-competitive CDK4/6i or CDK2i. NP-ALT blocks DNA replication in HR+ breast cancer (BC) cells and mouse models, but unlike CDK4/6i or CDK2i treatment, it induces ROS-dependent necroptosis to kill the tumor cells. This RIPK1/RIPK3-dependent cell death is more specific for HR+ lineages, but the combination of NP-ALT and palbociclib in TNBC cells causes synergy to induce necroptosis. We found that NP-ALT was still able to induce necroptosis in cell lines resistant to palbociclib, including those harboring genetic perturbations detected clinically in patients resistant to palbociclib. HR+ cell lines engineered to overexpress CDK6, FGFR, cyclin E, or cyclin D or ones that have loss of FAT1 or RB were still sensitive to NP-ALT. We tested other CDK2i, including CYC065, a CDK2/9 inhibitor and PF-06873600, a CDK4/6/2 inhibitor, and and found that while they were able to block DNA replication, only NP-ALT was able to induce ROS-dependent death in the resistant lines. We have shown that IpY reduces tumor volumes in resistant in vivo models as well, without causing adverse effects. Thus, NP-ALT and p27 targeting has several differentiators, which might provide clinical advantages: a) its low toxicity due to the tight specificity of the peptide for the p27 target and b) its ability to kill tumor cells as opposed to just causing cytostasis. Concarlo is currently developing NP-ALT into a therapeutic lead for the treatment of drug-resistant breast cancer. Citation Format: Stacy Wister Blain, Arianna Chand, Lina Pedraza-Ortiz, Allison VanInwegen, Lingyu Yan, Yun Wu, Grace Chen, Irina Jilishitz. NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to cause cell death in CDK4i-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1860.
Abstract 5089: <i>RNF43</i> mutation as a predictor of immunotherapeutic efficacy in colorectal cancer
Authors: Changjun Yu, Weibiao Kang, Yu Yuan, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai
Journal: Cancer Research (2022)

Abstract Background: RNF43, a single transmembrane circular E3 ubiquitin ligase, has been identified as a tumor suppressor for a variety of cancers, including ovarian cancer, gastric cancer, pancreatic cancer, endometrial cancer and colorectal cancer. It is even considered to be carcinogenic driver mutations in cholangiocarcinoma, ovarian cancer, gastric cancer, endometrial cancer and colorectal cancer (CRC). However, the correlation between RNF43 mutation and CRC immunotherapy has not been reported yet. Methods: We evaluated the role of RNF43 in CRC using publicly available data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). An in-house Chinese CRC cohort (n=2290) was used for the analysis of immune-related markers. The relationship between clinical pathologic features and RNF43 were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: In the MSKCC cohort, a total of 108 CRC patients receiving immunotherapy were enrolled, of which 38 (34.9%) were over 60-year-old and 61 (56.0%) were male. RNF43 mutation was significantly associated with high TMB and high MSI score (all p &amp;lt;0.05). Besides these, RNF43 mutation was discovered to be enriched in MSI instable. Kaplan-Meier survival analysis showed that patients with RNF43 mutation obtained better OS compared to RNF43 wild-type (not reach vs. 13 months, HR, 0.12; 95% CI 0.03-0.49; p=0.0034). In the TCGA cohort, CRC patients of stage I-IV were 16.6%, 38.5%, 28.2% and 14.2%, respectively. All of these patients received radiation therapy. No association was observed between RNF43 and OS (HR, 1.83; 95% CI 0.66-5.07; p=0.2479). In the in-house Chinese CRC cohorts, 210 (9.2%) patients carried RNF 43 mutations, of which 123 patients (58.6%) were male. RNF43 mutations were significantly associated with higher TMB levels (p&amp;lt;0.0001) and PD-L1 TPS&amp;gt; 1% (p=0.0110) in the in-house Chinese RCC cohorts. Citation Format: Changjun Yu, Weibiao Kang, Yu Yuan, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5089.
Abstract 1831: 9-ING-41, a glycogen synthase kinase 3B inhibitor targets TP53 in pediatric brain tumors ATRT and ETMR
Authors: Jason L. Haw, Elizabeth M. Moore, Kimberly McKinney, Karl Dykema, Abhinav Nagulapally, Nury Steuerwald, Giselle S. Sholler
Journal: Cancer Research (2022)

Abstract Purpose: The study aims to determine the activity of the blood brain barrier permeable glycogen synthase kinase 3B (GSK3B) inhibitor, 9-ING-41, in pediatric brain tumors: embryonal tumor with multilayered rosettes (ETMR) and atypical rhabdoid tumor (ATRT). Methods: ETMR cell line, BT183, was grown in ultralow attachment flasks and ATRT cell lines: ATRT-7316-2187, ATRT-787197, and CHLA02 were grown in suspension flasks. Cells were treated with 9-ING-41 at dose range (0-20µM). After 24 and 48 hours of 9-ING-41 cells were analyzed by western blot. After 72 hours of 9-ING-41 cell viability was assessed with Cell Titer Glo 2.0 and IC50s were analyzed by GraphPad. RNA seq was performed on cells after 12, 24, and 48 hours of 9-ING-41 treatment. Total RNA was isolated with miRNeasy Mini Kit. RNA integrity was evaluated by an Agilent 2100 Bioanalyzer profile. rRNA was selectively depleted by employing RiboZero Globin. Next generation sequencing libraries were prepared using an Illumina TruSeq Stranded Total RNA kits. Read mapping was performed using STAR in BaseSpace. DESeq2 was used for normalization and differential expression analysis. Ingenuity Pathway Analysis was performed. Results: The IC50s of 9-ING-41 in the cell lines BT183, CHLA02-ATRT, ATRT-787197, and ATRT-2187 are 145.5nM, 481.2nM, 503.1nM, and 528.3nM, respectively. In BT183 cells treated with 150nM 9-ING-41 for 48 hours, XIAP decreased significantly by 55% and cleaved caspase 3 increased significantly by 29-fold, quantified by densitometry. In addition, western blot showed a decrease in LIN28A and an increase in TP53 protein levels. RNA-seq data show an increase in the p53 signaling pathway in the ETMR BT183 cell line with z-scores of 2.53 and 3 (p=3.73x10-13 and 2.35x10-14) after 12 and 24 hours of 150nM 9-ING-41, respectively. In ATRT-787197 cells p53 signaling increased with z-scores of 1.0 and 2.236 (p=2.62x10-8 and 2.89x10-5) after 24 and 48 hours of 400nM 9-ING-41, respectively. RNA seq data also show the ability of 9-ING-41 to significantly increase the expression of CDK inhibitor, CDKN1A, and pro-apoptotic genes BBC3, DRAM1, and BAX in ETMR and ATRT while significantly decreasing stemness associated genes: SMO and GLI1 in ETMR. Conclusions: 9-ING-41 decreases ETMR and ATRT cell viability at clinically relevant concentrations and these doses increase the p53 pathway and induce apoptosis while reducing the expression of stemness associated genes. Citation Format: Jason L. Haw, Elizabeth M. Moore, Kimberly McKinney, Karl Dykema, Abhinav Nagulapally, Nury Steuerwald, Giselle S. Sholler. 9-ING-41, a glycogen synthase kinase 3B inhibitor targets TP53 in pediatric brain tumors ATRT and ETMR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1831.
Abstract 6209: TumOC: A tumor organoid-on-chip platform for real-time cell vitality measurements
Authors: Marie Flechner, Juergen Loskutov, Ulrike Pfohl, Katja Osman, Christian R. Regenbrecht, Katja Uhlig, Lena Wedeken
Journal: Cancer Research (2022)

Abstract Colorectal carcinomas (CRC) are one of the most common malignant tumors. Due to its heterogeneity and high probability to metastasize, the disease is often incurable and novel, improved therapies are needed. Enhanced, physiologically relevant in-vitro tumor models significantly increase the success rate in new drug development, reduce the number of animal experiments and result finally in better therapies for cancer patients. Furthermore, they have the potential to offer new approaches to personalized oncology. In recent years, 3D cell cultures were established as relevant preclinical cancer models, suitable for high-throughput-screening. However, their capacity to model and/or measure physiological processes can still be enhanced. In this project, we developed a tumor organoid-on-chip platform (TumOC) by combining most recent technological advances: We integrated patient-derived 3D cell cultures (organoids) from colorectal carcinomas and microsensor particles measuring oxygen concentration and therefore allowing assessment of cell vitality in real time in a microfluidic system. The resulting TumOC platform allows for defined exposition of cytostatic drugs including dynamic treatments. Measurements of cell vitality in real time enables analysis of not only the final effect of a drug treatment, but also the kinetics of drug response. At the same time, utilizing organoids allows for recapitulating tumor architecture and heterogeneity. Here we report the first proof of principle results generated with this system. We measured the cell vitality in real time over 72 hours during treatment with classic chemotherapeutics or targeted cancer drugs and compared the results to end-point measurements on the same organoids in a static system. In conclusion, our TumOC platform with its ability to recapitulate tumor heterogeneity in combination with dynamic treatments and real-time cell vitality assessment is an in-vitro tumor model closely recapitulating the physiological situation in a patient. TumOC provides an impressive opportunity to test and, consequently, predict the effectiveness of anti-cancer therapies. Therefore, this system is of interest not only for pre-clinical drug development but also for personal oncology. Citation Format: Marie Flechner, Juergen Loskutov, Ulrike Pfohl, Katja Osman, Christian R. Regenbrecht, Katja Uhlig, Lena Wedeken. TumOC: A tumor organoid-on-chip platform for real-time cell vitality measurements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6209.
Abstract 3233: Interleukin enhancer-binding factor 2 amplification controls mRNA stability and enhances DNA damage response in metastatic melanoma
Authors: Xiaoqing Zhang, Matias A. Bustos, Rebecca Gross, Romela Irene Ramos, Teh-Ling Takeshima, Gordon B. Mills, Qiang Yu, Dave S. Hoon
Journal: Cancer Research (2022)

Abstract Background: 1q21.3 amplification is frequently observed in metastatic melanoma. Interleukin enhancer-binding factor 2 (ILF2) is in the 1q21.3 amplified region. The functional role of ILF2 as well as its contribution in promoting an aggressive phenotype in cutaneous metastatic melanoma is unknown. Methods: In silico analyses were performed using the TCGA SKCM dataset with clinical annotations. The results were validated in three melanoma cohort microarray datasets from the GEO database. Melanoma tissues mRNA levels were assessed by RNA in situ hybridization and protein levels were analyzed by immunohistochemistry. Four stable metastatic melanoma cell lines were established for in vitro ILF2 functional characterization. Results: Our results showed that the ILF2 copy number variation (CNV) is positively correlated with ILF2 mRNA expression (r=0.68, p&amp;lt;0.0001). Additionally, ILF2 mRNA expression significantly increased with melanoma progression (p&amp;lt;0.0001) and is significantly associated with poor overall survival in metastatic melanoma patients (p=0.026). In vitro, ILF2 overexpression (ILF2-OV) enhances cellular proliferation, whereas ILF2 knockdown decreases cellular proliferation by blocking the cell cycle. Mechanistically, we demonstrated the interaction between ILF2 and the splicing factor U2AF2. Reinforcing their functions as a complex, the U2AF2 knockdown reverses the cellular proliferation effects mediated by ILF2-OV. The levels of U2AF2 mRNA and protein levels increased during melanoma progression. Stage IIIB-C melanoma patients with high ILF2-U2AF2 expression showed significantly shorter overall survival (p=0.024). Functional assays showed that enhanced ILF2/U2AF2 expression promotes a more efficient DNA-damage repair by increasing RAD50 and ATM mRNA expression. Paradoxically, metastatic melanoma cell lines with ILF2-OV were more sensitive to ATM inhibitors. Conclusion: Our study uncovered that the ILF2 and U2AF2 complex may have biological implications in controlling the mRNA stability of RAD50 and ATM in metastatic melanoma. Clinically, ILF2 amplification is associated with melanoma progression, triggers a functional downstream pathway in metastatic melanoma that promotes DNA damage repair, and increases the sensitivity to ATM inhibitors. Citation Format: Xiaoqing Zhang, Matias A. Bustos, Rebecca Gross, Romela Irene Ramos, Teh-Ling Takeshima, Gordon B. Mills, Qiang Yu, Dave S. Hoon. Interleukin enhancer-binding factor 2 amplification controls mRNA stability and enhances DNA damage response in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3233.
Abstract 28: New onset of type 2 diabetes after colorectal cancer diagnosis: Results from three prospective US cohort studies, systematic review, and meta-analysis
Authors: Hongmei Zeng, Chen Yuan, Jakub Morze, Ruiying Fu, Kai Wang, Liang Wang, Feng Sun, John S. Ji, Edward L. Giovannucci, Mingyang Song
Journal: Cancer Research (2022)

Abstract Background: Limited data indicate that patients with colorectal cancer (CRC) are at higher risk of developing type 2 diabetes (T2D). We prospectively examined the risk of T2D between individuals with and without CRC in three large cohorts and conducted a meta-analysis. Methods: We assessed the diagnosis of CRC and T2D among 111 485 women from the Nurses' Health Study, 112 958 women from the Nurses' Health Study II, and 46 581 men from the Health Professionals Follow-up Study. We used multivariable Cox regression with time-varying covariates to calculate the hazard ratio (HR) of T2D in relation to CRC diagnosis. We further performed a systematic review and meta-analysis of cohort studies. Findings: Up to 36 years of follow-up (6.9 million person-years), we documented 3402 incident CRC cases and 26 469 T2D cases. Compared to non-CRC individuals, those with CRC were more likely to develop T2D (multivariable-adjusted HR 1.20, 95% CI 1.05-1.38). The association was most evident for individuals with fewer risk factors for T2D. In the meta-analysis of seven cohort studies (1 061 744 participants), CRC was associated with higher T2D risk (meta-analysis HR 1.21, 95% CI 1.11-1.31, I2=57.9%). By CRC duration, a statistically significant association was observed in the first 10 years but not after 10 years of CRC diagnosis (≤5 years, meta-analysis HR 1.32, 95% CI 1.27-1.36; 5.1-10 years, 1.14 [1.04-1.25]; &amp;gt;10 years, 1.14 [0.91-1.37]). Interpretations: CRC was associated with increased T2D risk, especially in the first ten years after CRC diagnosis. Our findings highlight the importance of T2D prevention for CRC survivorship care. Citation Format: Hongmei Zeng, Chen Yuan, Jakub Morze, Ruiying Fu, Kai Wang, Liang Wang, Feng Sun, John S. Ji, Edward L. Giovannucci, Mingyang Song. New onset of type 2 diabetes after colorectal cancer diagnosis: Results from three prospective US cohort studies, systematic review, and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 28.
Abstract 1414: Assessment of the Cancer Testis antigen AKAP4, via tumor expression analysis and IHC, as a potential vaccine and immunotherapy target for colorectal cancer
Authors: Chandana S. K. Herath Mudiyanselage, Neil Mitra, Otavia L. Caballero, Dasuni N. Gamage, Xiaohong Yan, Vesna Cekic, Joseph Martz, Richard L. Whelan
Journal: Cancer Research (2022)

Abstract Introduction: Cancer-Testis antigens (CTA’s) are normally expressed in germline tissue, however, aberrant expression occurs in some cancers. Restricted CTA expression in normal tissues make CTA’s potential vaccine targets. CTA’s have been associated with tumor cell proliferation and invasion. The CTA A-kinase anchor proteins 4 (AKAP 4) plays a role in cancer development and progression. The expression pattern of AKAP4 gene in CRC is not well characterized. This study’s aim was to assess AKAP4 expression in CRC and to assess this CTA’s potential as a vaccine target. Methods: CRC patients (pts) undergoing surgery who donated tissue to an IRB approved tissue/data bank comprise the study group. Demographic and pathologic data were assessed. Tissues were OCT embedded and stored at -800C. Total purified RNA was isolated from tissue samples and cDNA synthesized. AKAP4 expression was analyzed by quantitative PCR (QPCR) using EXPRESS qPCR universal Supermix and Taqman assay. Comparative quantitative analysis was performed based on the delta-delta Ct method with GAPDH as internal control. Tumor and testis AKAP4 expression levels were determined; tumors with levels 0.1% or more than the testis was considered positive. Immunohistochemistry (IHC) was performed on a subset of tumor and normal tissue. The impact of tumor location and cancer stage on AKAP4 expression was determined and assessed (Wilcoxon signed rank test). Results: 70 paired CRC and normal tissue specimens (35 M/36 F, age 67.8±14) were studied (86% colon,14% rectal; cancer stage: 1, 24%; 2,37%; 3, 31.%;stg 4, 7%). The percent of pts with a relative Malignant to Normal tissue AKAP4 expression ratio (MN) over 1 was 17%; the percent with both MN ratio over 1 and expression levels above 0.1% of testis levels was 16%. IHC demonstrated AKAP4 in a subset of CRC tumor samples. No significant difference was noted between colon vs rectal, or cancer stage groups. No expression was found in 21 normal samples. Discussion: In a tumor subset the relative expression of AKAP4 was above that of normal colon and more than 0.1% of testis expression. IHC study demonstrated the antigen in CRC tumors. A larger study is needed determine if AKAP4 expression correlates with T, N, or final tumor stage. AKAP4 holds some promise as a vaccine target. Citation Format: Chandana S. K. Herath Mudiyanselage, Neil Mitra, Otavia L. Caballero, Dasuni N. Gamage, Xiaohong Yan, Vesna Cekic, Joseph Martz, Richard L. Whelan. Assessment of the Cancer Testis antigen AKAP4, via tumor expression analysis and IHC, as a potential vaccine and immunotherapy target for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1414.
Abstract 1672: Effect of BCOR loss in <i>Xenopus laevis</i> and <i>tropicalis</i>: Insights for retinal development and retinoblastoma
Authors: Michelle Garying Zhang, Dawn Owens, Nicole Jones, Daniel Pelaez, J. William Harbour
Journal: Cancer Research (2022)

Abstract Retinoblastoma is the most common pediatric eye cancer, accounting for approximately 11% of cancers within the first year of life. Almost all retinoblastoma tumors are initiated by bi-allelic mutational inactivation of RB1, yet there is a broad range of clinical presentations, suggesting the existence of secondary driver events in cancer progression. Genomic analysis identified BCOR as the second most commonly mutated gene in retinoblastoma. There is growing evidence that inactivating BCOR mutations are associated with more aggressive features, such as dedifferentiation, vitreous seeding, optic nerve invasion, and worse patient outcomes. Unfortunately, little is known about the function of BCOR in the retina and the effects of BCOR loss in retinoblastoma. Here, we used Xenopus laevis and tropicalis models to study the role of BCOR in normal ocular and retinal development. In both models, targeted depletion of BCOR in cell lineages giving rise to the eye resulted in a discrete microphthalmia phenotype. Furthermore, we developed in situ hybridization tools for probing characteristic retinal lineage-specific genes and performed histology to compare structural differences. We provide evidence that BCOR normally regulates critical steps in retinal developmental, suggesting that loss of BCOR in retinoblastoma may drive tumor progression by disrupting this function. Citation Format: Michelle Garying Zhang, Dawn Owens, Nicole Jones, Daniel Pelaez, J. William Harbour. Effect of BCOR loss in Xenopus laevis and tropicalis: Insights for retinal development and retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1672.